Colorectal cancer is the second leading cause of cancer-related deaths in the U.S. Based on a number of epidemiological studies, the use of a daily non-steroidal anti-inflammatory drug (NSAID) is associated with a significant reduction in risk for colorectal cancer. However, the chronic use of this drug class is limited due to the adverse actions of NSAIDs to induce gastrointestinal bleeding/ulceration in susceptible patients, which in some cases results in life-threatening hemorrhage. The main goal of this proposal is to test two new drugs, which are members of a novel class of phosphatidylcholine (PC)-associated NSAIDs for chemopreventive activity, ibuprofen (IBU- PC) and indomethacin (INDO-PC) that have been documented in preclinical studies and a pilot clinical trial (IBU-PC) to be safer to the GI mucosa than the unmodified NSAID. An established model of colon cancer in which rodents are administered the chemical carcinogen (azoxymethane) will be used to test the chemopreventive efficacy of IBU-PC and INDO-PC versus the unmodified NSAIDs (if administered before or after AOM exposure) to inhibit, at the completion of the 5-6 week study period, the number and multiplicity of colonic aberrant crypt foci (ACF). Measures of GI bleeding and injury will be assessed at euthanasia to assess the GI safety of the test formulations. We will also investigate a number of potential mechanisms of drug action in which IBU-PC and INDO-PC inhibit the early stages of colon cancer progression including: inhibition of: cyclooxygenase (COX) activity, reducing the expression of COX-1, COX-2 and mdr-1; and their ability to disrupt Ras-signaling events. These studies will establish the feasibility of using IBU-PC or INDO-PC for chemoprevention while lowering the risk of adverse GI events, resulting in the development of one or more efficacious and safe drugs for prevention of colorectal cancer. PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer-related deaths in the U.S. There is sufficient clinical information available to support the use of nonsteroidal anti-inflammatory drugs (NSAIDs) as chemopreventive agents in patients at risk for this disease, but the side effect of this class of drugs to cause bleeding and ulceration of the gastrointestinal (GI) tract, limits their widespread use. The drugs under development in this proposal are Ibuprofen and Indomethacin that are chemically complexed with a lipid (phosphatidylcholine) to make them much safer for the GI tract, while still maintaining their chemopreventive action. Ibuprofen-PC and Indomethacin-PC have the potential to save healthcare dollars by providing relatively low cost drugs that can prevent a fatal disease (colorectal cancer) and also avoid life-threatening side effects (bleeding).